The drug discovery landscape is rapidly changing and with it comes the need to generate leads with lower attrition rate. Property-based drug design approach is guiding researchers in designing candidates with the right balance of physicochemical properties - safety and absorption, distribution, metabolism, and excretion (ADME) profiles. 4th Annual Property-Based Drug Design in Medicinal Chemistry conference will bring together experts and leaders from industry and academia to share strategies and case studies for new and non-traditional molecules, how computational modeling and data management can be used effectively, and to discuss novel ways to measure or predict properties to make molecules more drug-like and overcome challenges in discovery, development, and the clinic.

Macrocycles are found widely in nature and several are marketed as drugs with good drug-like properties. This presentation will illustrate how Ensemble can rapidly generate millions of synthetic macrocycles using DNA-programmed chemistry, and how they are efficiently screened against protein-protein interaction targets to identify hit compounds and SAR. The novel approach will be illustrated with successful examples of lead discovery programs, including the discovery of novel XIAP and IL17A antagonists.

Astex has successfully applied fragment-based drug design to protein-protein interaction targets. Key factors in this success have been (i) detailed structural understanding of binding interactions between fragment and target protein via x-ray crystallography and (ii) rigorous control of physicochemical properties. The approach is exemplified by Astex’s Inhibitor of Apoptosis Protein (IAP) project, where potent dual antagonists of XIAP and cIAP1 were identified, having in vivo anti-tumor activity.

A great deal of progress has been made in recent years in elucidating design principles for achieving favorable ADME properties in Beyond Rule-of-5 macrocycles. Many of the important principles, such as minimization of exposed polar surface area to improve permeability, are dependent upon the overall 3D structure, which can be computationally predicted and confirmed experimentally. Here we present computational approaches and property/ADME trends seen in a variety of interesting macrocyclic chemotypes.

Lead optimization is not a simple one-dimensional optimization of affinity and effective computational tools should allow of optimization of other molecular properties. We will present BROOD v 2.1 a fragment-based R-group and template replacement lead optimization application that can suggest replacement groups that are simultaneously optimized for many different properties at once. Several examples to demonstrate this unique ability will be presented.

For drugs actively transported across the blood-brain barrier, unbound plasma and unbound brain concentrations differ to an extent that is commonly unknown. We report on approaches to assess and predict unbound brain concentration for P-gp substrates and how they can be utilized in early CNS drug discovery to enhance the understanding of PK/PD relationships and support a clinically meaningful compound optimization.

Designing compounds with suitable properties for inhalation present unique challenges to the medicinal chemist. This talk will discuss a number of programs from within Pfizer that have addressed this issue, across numerous target classes, to produce inhaled candidate drug molecules for the treatment of various lung diseases – Inhibition of GPCRs, PDEs and Kinases have been targeted successfully via this approach.

5:45 Discovery of Asunaprevir (BMS-650032): An Approved NS3 Protease Inhibitor for the Treatment of Hepatitis C

Hepatitis C Virus (HCV) infection is an insidious liver disease that affects more than 170 million people worldwide. The HCV NS3/4A protease is an essential enzyme for viral replication and, as such, has been validated as a target for anti-HCV therapy in clinical trials. In this presentation, the discovery of BMS-650032, a potent and selective inhibitor of the NS3/4A enzyme, recently approved for treatment of HCV, will be described. Highlights of this discovery process include the design of the acylsulfonamide chemotype, as well as optimization of ADME and toxicology properties within this chemical series.

Each discussion group in this session is led by a moderator/s who ensures
focused conversations around key issues. Attendees join a specific group and
the small, informal setting facilitates sharing of ideas and active networking.

I will draw the distinction between hypothesis-driven and
prediction-driven molecular design before questioning some of
the assumptions commonly made in drug discovery. Alternatives
to the octanol/water partitioning system will be discussed and relationships
between structures will be outlined as a framework for analyzing biological
activity and physicochemical properties.

Analysis of drugs and clinical candidates having MW >500 Da demonstrate significant opportunities for discovery of cell permeable and orally bioavailable drugs in physicochemical space far beyond the rule of 5 (bRo5). As compared to Ro5 compliant drugs, those bRo5 may modulate different kinds of targets, in particular ones having flat and groove shaped binding sites. Interestingly, macrocycles appear to have features that provide special opportunities in bRo5 drug space.

In this work, a high throughput chromatographic phosphatidylcholine (PC) affinity assay has been demonstrated to offer an insight into the prediction of compound promiscuity, non-specific binding and phospholipidosis-inducing potential (PLIP) of pharmaceuticals. Results will include >1000 compound study comparing PC affinity to generic compound promiscuity "Target Hit Rate" assay and the benefit of this approach over cLogP. Results will also be presented on how his assay has been a useful tool to predict for non-specific binding for PET ligand tracers and PLIP.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Known Unknowns in Drug Discovery Data

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC

Data drives Drug Discovery research at all levels and determine the outcome of many thousands of decisions that govern the progress, success, or failure of any one project. Yet, even the ‘experimental’ error of this data is often unknown, under-utilized, or unconfirmed and the actual error has been shown to be even larger that that. This includes physical property data as well as that from assays, biomolecular structure determination, and computational modeling. These errors, their magnitude and genesis will be discussed with a eye toward informed decision making.

11:30 Physicochemical and Biomimetic Properties to Guide Lead Optimization

Measurements of physicochemical and biomimetic properties in early drug discovery are used for the estimation of in vivo distribution and drug efficiency. The Drug Efficiency Index (DEI) (potency plus drug efficiency) has been shown to be proportional to receptor occupancy. Simultaneous optimization of potency and drug efficiency can help guide candidate selection toward compounds of increased quality and with reduced chance of later stage failures.

Hepatobiliary transport is a major disposition pathway, and estimating its contribution to the total systemic clearance is extremely valuable for predicting clinical pharmacokinetics and understanding the possible mechanisms of hepato-biliary toxicity and potential drug-drug interactions. Furthermore, the clinical importance of hepatic drug transporters has attracted potential design strategies to support liver targeting – a key approach to maximizing the potential therapeutic index of a compound. Early assessment of drug exposure (PK) is challenging in this space given the limited information regarding the specific transporter expression levels, lack of established IVIVE and lack of sizable datasets. This presentation provide insight into the hepato-biliary transport with relevance to exposure optimization and the current understanding of the physicochemical and structural drivers in order to facilitate rational drug design.

2:05 A Systems Pharmacokinetics Approach to the Optimization of Drug Properties to Help Maximize Therapeutic Index: On the Quantitative Prediction of Unbound Tissue Distribution and its Implication for Drug Design

In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide–mediated hepatic uptake and impaired passive distribution to the pancreas is described.

2:35 Utilizing Physiologically Based Pharmacokinetic Modeling to Inform Formulation and Clinical Development

Physicochemical properties and early ADMET assays guide chemotype evaluation and rational scaffold alteration. This presentation will focus on the integration of these approaches with physiologically based pharmacokinetic modeling (PBPK) to enable the prediction of clinical outcomes and to optimize selection of formulation.

3:05 The Discovery and Development of an HIV-1 Attachment Inhibitor Clinical Candidate

The inhibition of the attachment of the HIV-1 viral glycoprotein gp-120 to the host cell receptor CD4 during the first step of the viral entry represents a novel antiretroviral approach. This talk will discuss the modifications made by medicinal chemists based on clinical feedback from multiple compounds, discuss a successful prodrug approach, and describe formulation development leading to a clinical candidate that is currently progressing to Phase III studies.